Immune system protein starves 'staph' bacteria

The protein turned out to be calprotectin, which was discovered as a calcium-binding protein about 20 years ago and is known to inhibit bacterial and fungal growth in test tubes. But how it kills bugs was unclear.

The team demonstrated in a series of in vitro and in vivo experiments that calprotectin inhibits staph growth and that it does this by binding – chelating – nutrient metals, specifically manganese and zinc.

“It basically starves the bacteria by stealing its food,” Skaar said.

Calprotectin makes up about half of the internal content of neutrophils, the primary immune cells that respond to a staph infection. The investigators propose that calprotectin is a second weapon neutrophils employ as they wage battle in the abscess. First, neutrophils try to “gobble up” the bacteria. If they fail and die (staph is expert at secreting toxins that kill neutrophils), then they spill their guts, which are filled with metal-binding calprotectin sponges that soak up the metals.

“The neutrophil gets the last laugh,” Skaar quipped.

“The work is a phenomenal merger of several cutting edge technologies, which collectively allow an unprecedented view of the host-pathogen interface,” said Paul Dunman, Ph.D., assistant professor of Pathology and Microbiology at the University of Nebraska Medical Center, and a co-author of the Science paper. “This discovery could lead to a new way to treat staph infections.”

The findings suggest that drugs that bind metals – like calprotectin does – would make good antibiotics.

“If we can figure out how to make a molecule that transiently binds metals, and that can be targeted to abscesses, I think that would be a great drug,” Skaar said.

Walter Chazin, Ph.D., Richard Caprioli, Ph.D., and members of their teams at Vanderbilt were key to the studies, as were collaborators at the University of Aberdeen, Scotland, the University of Nebraska Medical Center, the University of Muenster, Germany, and Applied Speciation and Consulting in Washington. The research was supported by the Searle Scholars Program, the Burroughs Wellcome Fund, the National Institutes of Health, and the Department of Defense.